On planet earth, organisms have evolved mechanisms to synchronize metabolic and physiological functions with the ~24 hour light/dark cycle. Interestingly, many human diseases have associations with the circadian day. When traveling across time zones, our sleep-wake patterns, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of being out of phase until we adjust to the new time zone. In addition, recent studies have also linked disruption of the circadian clock with numerous ailments, including: asthma, cancer, cardiovascular diseases, and learning disorders. Tremendous knowledge has come from studying the genetic and molecular basis of circadian rhythms in model organisms. Despite the importance of the circadian clock to all aspects of our physiology and behavior, the opportunity to probe the human circadian clock only became possible with the recognition of Mendelian circadian variants in people (familial advanced sleep-phase, FASP). In the previous funding periods of this grant, we characterized FASP, collected many families, and mapped and cloned the first FASP gene. We went on to identify a total of 5 FASP genes and have generated animal models of all of them. We also described Familial Natural Short Sleep (FNSS) and have cloned the first human sleep gene/mutation. During the current grant period, we ve 1) done extensive work in characterizing the proteomics of circadian kinases CKI, CKI, and GSK3; 2) identified mutations in CRY2 and TIMELESS causing FASP and generated mouse models; 3) characterized the role of PKC in the food entrainable oscillator; 4) Demonstrated that circadian mutations in CKI also cause migraine with aura. In this competitive renewal, we propose to collect additional families (Aim 1), to perform whole exome sequencing in probands from 50 unexplained FASP families (Aim 2), and to sift among the many variants to identify novel circadian rhythm/FASP genes/mutations (Aim 3). Parallel studies in humans and mouse models will synergize in dissecting understanding of FASP in humans and exploring the similarities and differences between our circadian clocks vs. those of other organisms. Studying the molecular mechanism of human circadian rhythmicity will have an enormous impact on our understanding of human health & disease. It should also lead to new strategies for pharmacological manipulation of the human clock to improve the treatment of jet-lag, various clock-related sleep and psychiatric disorders, as well as other human diseases. Understanding of the human clock genes and mutations will enable development of better therapies for ASPS of aging, jet lag, and other sleep disorders.